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Who am I? That is a question the rest of you could probably answer better than I. I am a wife, mother, daughter, sister, friend, pediatric nurse practitioner, cook, teacher, gardener, lover of words and music, occasional seamstress, and homemaker. I do have a couple of talents of questionable merit: I can create a decent meal in less than 30 minutes. I can feed and/or soothe almost any baby. And I can remember practically any song I've ever heard. For the rest, I'd rather those who know me decide.

Thursday, May 25, 2017

Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS

Since it was double skirt day....I decided to go ahead and make it a double post day!!!!
To continue the subject of BRAFi -

From The coBRIM trial - August 2016 we learned - that when cobinmetinib and vemurafinib were combined, the median overall survival (OS) was 22.3 months and the median progression free survival (PFS) was 12.3 months.

The
combination of the BRAF inhibitor encorafenib and the MEK inhibitor
binimetinib reduced the risk of disease progression or death by 23%
compared with single-agent encorafenib for patients with BRAF-mutant
melanoma, according to findings from part 2 of the phase III COLUMBUS
trial. The median
progression-free survival (PFS) for patients treated with the
combination was 12.9 months compared with 9.2 months for patients
receiving encorafenib alone. Based
on these data, along with previously reported findings from part 1 of
the COLUMBUS trial, the developer of the combination, Array
BioPharma, anticipates filing a new drug application with the FDA in
June or July.

The COLUMBUS trial included 921 patients with
locally advanced, unresectable, or metastatic BRAFV600-mutant
melanoma. Prior treatment with immunotherapy was allowed. Those with
untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and
mucosal melanoma were excluded from the trial.[Why the hell not????
You could put them in their own separate group, so as not to sully
your results Array CEO person!!! And still give them access to the
drug!]

In part 1 of the study, 577 patients were randomized in
a 1:1:1 ratio to receive encorafenib plus binimetinib, encorafenib
alone, or vemurafenib alone. In the combination arm, encorafenib was
administered at 450 mg daily and binimetinib was administered at 45
mg twice daily. Single-agent encorafenib was given at 300 mg daily.
Vemurafenib was administered at 960 mg twice daily. Part 2 of
the study randomized 344 patients in a 3:1 ratio to receive
encorafenib plus binimetinib at 45 mg twice daily or encorafenib
alone. Encorafenib was given at 300 mg daily. “Part 2 was
designed specifically to assess the contribution of binimetinib to
the combination of binimetinib and encorafenib by reducing the dose
of encorafenib to 300 mg in the combination arm to allow for a
comparison of equal doses across arms,” Array wrote in a press
release.In
Part 1 of the study, the median PFS was 14.9 months with the
combination of encorafenib and binimetinib compared with 7.3 months
for vemurafenib alone.
The improvement in PFS represented a 46% reduction in the risk of
progression or death. [That's good, but of course we have learned
never to give vemurafenib, a BRAF inhibitor without a MEK inhibitor!!! So that's a bit of a false
comparison!]When
single-agent encorafenib was compared with the combination arm the
difference between the groups did not reach statistical significance.
However, median PFS with encorafenib was statistically superior to
vemurafenib. Findings for overall survival (OS) were not yet
available. [hmmmmmm.....]

The
objective response rate (ORR) with the combination was 63% versus 40%
with vemurafenib.[Again...not comparing apples to apples...we KNOW that response rates are better with a BRAF/MEK combo!!!]With single-agent encorafenib, the ORR was 51%.[This fact can at least be compared to single agent vemurafenib response rate of 40%.]The
complete response rate was 8% with the combination versus 5% and 6%
with encorafenib and vemurafenib, respectively. The median duration
of response was 16.6 months with the combination versus 14.9 months
with encorafenib and 12.5 months with vemurafenib.

By local
review, median PFS with the combination was 14.8 versus 7.3 months
with vemurafenib. The ORRs by local review were 75% for the
combination versus 49% and 58% for vemurafenib and encorafenib
monotherapy, respectively. In this assessment, the combination
was superior to single-agent encorafenib. The median PFS with
encorafenib was 9.2 months, which was also superior to single-agent
vemurafenib.

Grade
3/4 AEs were experienced by 58% of patients treated with the
combination versus 66% and 63% with encorafenib and vemurafenib,
respectively.[As previously demonstrated, side effects were DECREASED with a BRAF/MEK combo.]The most common grade 3/4 AEs with the combination were
gamma-glutamyltransferase, increased blood creatine phosphokinase,
and hypertension. Time to first grade 3/4 AE was long with the
combination, at 2.5 months versus 0.4 months for encorafenib and 1.3
months for vemurafenib.

In
March, Array withdrew its FDA new drug application for single-agent
binimetinib as a treatment for patients with NRAS-mutant
advanced melanoma, based on feedback from the FDA during a preplanned
review meeting. [So I gather they are going to market this only for BRAF positive folks, rather than NRAS mutant.] The
application for binimetinib was based on data from the phase III NEMO
study, which was presented at the 2016 ASCO Annual Meeting. In the
open-label study, PFS with binimetinib was 2.8 versus 1.5 months with
dacarbazine, representing a 38% reduction in the risk of progression
or death; however, OS was not improved with the MEK inhibitor.
[Pretty sad if you can't beat dacarbazine!]

Okay. My synopsis is this: Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS. This combo showed a PFS of 14.9 months. Objective response rate was 63% with the comb0. There was an ORR of 51% to encorafenib alone. Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending. OS data for encorafenib/binimetinib has not yet been reported. OS in most other BRAF/MEK combo's is around 2 years. The combo discussed here demonstrated fewer side effects than when the BRAFi component was used alone....which is consistent with other reports using a BRAF/MEK combo vs BRAFi alone.

PFS of 14.9 months is better than 12. Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!) We'll have to see what the OS data shows and if these current figures hold in future cohorts. Hang tough ratties. You will save us all. - c